Trial Outcomes & Findings for SGLT2 Inhibition in Combination With Diuretics in Heart Failure (NCT NCT03226457)

NCT ID: NCT03226457

Last Updated: 2021-06-30

Results Overview

Change from urinary volume from baseline (mls).

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 23 participants
• Primary outcome timeframe: Change from baseline to 6 weeks
• Results posted on: 2021-06-30

Participant Flow

Participant milestones

Measure	Empagliflozin/Placebo Treatment Sequence: Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. Minimum of a 2 week washout period. 6 weeks of placebo	Placebo/Empagliflozin Treatment Sequence: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. Minimum of 2 week washout period 6 weeks of Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily
Treatment 1: 6 Weeks STARTED	12	11
Treatment 1: 6 Weeks COMPLETED	12	11
Treatment 1: 6 Weeks NOT COMPLETED	0	0
Washout Period: Minimum 2 Weeks STARTED	12	11
Washout Period: Minimum 2 Weeks COMPLETED	12	11
Washout Period: Minimum 2 Weeks NOT COMPLETED	0	0
Treatment 2: 6 Weeks STARTED	12	11
Treatment 2: 6 Weeks COMPLETED	12	11
Treatment 2: 6 Weeks NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

SGLT2 Inhibition in Combination With Diuretics in Heart Failure

Baseline characteristics by cohort

Measure	Baseline Characteristics n=23 Participants N = 23, Crossover study design. Baseline characteristics
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=5 Participants
Age, Categorical >=65 years	18 Participants n=5 Participants
Age, Continuous	69.8 years STANDARD_DEVIATION 5.7 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	23 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United Kingdom	23 participants n=5 Participants

PRIMARY outcome

Timeframe: Change from baseline to 6 weeks

Change from urinary volume from baseline (mls).

Outcome measures

Measure	Empagliflozin n=23 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
The Effect of Empagliflozin Versus Placebo on the Change in Urine Output.	545 mL Interval 136.0 to 954.0	-113 mL Interval -345.0 to 119.0

SECONDARY outcome

Timeframe: Change from baseline to 6 weeks

The effect of empagliflozin versus placebo on the change in urinary sodium excretion: change in fractional urinary sodium excretion from baseline (%).

Outcome measures

Measure	Empagliflozin n=23 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion.	0.11 percentage of change in FENa Interval -0.22 to 0.44	-0.00 percentage of change in FENa Interval -0.19 to 0.19

SECONDARY outcome

Timeframe: From baseline to 6 weeks

The effect of empagliflozin versus placebo on the change in glomerular filtration rate: Change in estimated glomerular filtration rate from baseline (ml/min/1.73m2).

Data was recorded as a persistent reduction in CKD category in the empagliflozin group versus placebo

Outcome measures

Measure	Empagliflozin n=23 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate	6 Participants	5 Participants

SECONDARY outcome

Timeframe: Change from baseline to 6 weeks

Change in serum creatinine from baseline (mmol/L).

Outcome measures

Measure	Empagliflozin n=23 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine.	-0.44 mmol/L Interval -8.82 to 7.94	-10.81 mmol/L Interval -19.2 to -2.44

SECONDARY outcome

Timeframe: Change from baseline to 6 weeks

The effect of empagliflozin versus placebo on the change to urinary protein/creatinine ratio: Change in urinary protein/creatinine ratio from baseline (mg/mmol).

Outcome measures

Measure	Empagliflozin n=12 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=11 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio.	2.26 mg/mmol Interval -1.75 to 6.28	-3.05 mg/mmol Interval -7.05 to 0.97

SECONDARY outcome

Timeframe: Change from baseline to 6 weeks

The effect of empagliflozin versus placebo on the change to urinary albumin/creatinine ratio: Change in urinary albumin/creatinine ratio from baseline (mg/mmol).

Outcome measures

Measure	Empagliflozin n=23 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio.	1.18 mg/mmol Interval -0.69 to 3.05	-1.1 mg/mmol Interval -2.98 to 0.77

SECONDARY outcome

Timeframe: Change from baseline to 6 weeks

The effect of empagliflozin versus placebo on the change to the renal biomarker, cystatin C: Change in Cystatin C from baseline (ng/ml).

Outcome measures

Measure	Empagliflozin n=23 Participants Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 Participants Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C.	31.35 ng/ml Interval -80.07 to 142.75	22.5 ng/ml Interval -91.52 to 136.52

Adverse Events

Empagliflozin

Serious events: 2 serious events

Other events: 1 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	Empagliflozin n=23 participants at risk Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 participants at risk Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
Cardiac disorders Hospitalization with heart failure following discontinuation of investigational medicinal product	8.7% 2/23 • Number of events 2 • For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total. Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected. As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.	0.00% 0/23 • For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total. Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected. As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.
Cardiac disorders Hypotension	4.3% 1/23 • Number of events 1 • For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total. Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected. As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.	0.00% 0/23 • For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total. Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected. As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.

Other adverse events

Measure	Empagliflozin n=23 participants at risk Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.	Placebo n=23 participants at risk Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.
Musculoskeletal and connective tissue disorders Gout	4.3% 1/23 • Number of events 1 • For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total. Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected. As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.	8.7% 2/23 • Number of events 2 • For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total. Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected. As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.

Additional Information

Dr Natalie Mordi (Principle Investigator)

University of Dundee

Phone: + 44 (0) 1382 383 667

Email: n.a.mordi@dundee.ac.uk

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place